ABSTRACT

Context Electrocardiographic left ventricular hypertrophy (LVH) is a strong
predictor of cardiovascular (CV) morbidity and mortality. However, the predictive
value of changes in the magnitude of electrocardiographic LVH criteria during
antihypertensive therapy remains unclear.

Objective To test the hypothesis that lesser severity of electrocardiographic
LVH during antihypertensive treatment is associated with decreased CV morbidity
and mortality, independent of blood pressure levels and reduction and treatment
modality.

Design, Setting, and Participants Double-blind, randomized, parallel-group study conducted in 1995-2001
among 9193 men and women with hypertension aged 55 through 80 years (mean,
67 years), with electrocardiographic LVH by Cornell voltage-duration product
or Sokolow-Lyon voltage criteria and enrolled in the Losartan Intervention
For Endpoint Reduction in Hypertension (LIFE) study.

Main Outcome Measure Composite end point of CV death, myocardial infarction (MI), or stroke
in relation to severity of electrocardiographic LVH determined at baseline
and on subsequent electrocardiograms obtained at 1 or more annual revisits.

Conclusions Less-severe electrocardiographic LVH by Cornell product and Sokolow-Lyon
voltage criteria during antihypertensive therapy is associated with lower
likelihoods of CV morbidity and mortality, independent of blood pressure lowering
and treatment modality in persons with essential hypertension. Antihypertensive
therapy targeted at regression or prevention of electrocardiographic LVH may
improve prognosis.

Figures in this Article

Left ventricular hypertrophy (LVH) detected by 12-lead electrocardiogram
(ECG)1- 3 and by
echocardiography4- 8 are
common manifestations of preclinical cardiovascular (CV) disease that strongly
predict CV morbidity and mortality. Antihypertensive therapy aimed at reducing
blood pressure (BP) can produce regression of LVH3,4,9- 15 and
reduces but does not entirely eliminate the increased risk of major CV events.16- 20 However,
whether regression of electrocardiographic LVH per se is associated with improved
prognosis independent of improvements in BP during antihypertensive therapy
requires further evaluation.2,3,12,13

Usefulness of electrocardiographic criteria for the detection of LVH
and for serial evaluation of changes in left ventricular mass has been limited
by low sensitivity of standard voltage criteria for the detection of anatomic
LVH.21- 27 However,
Cornell voltage criteria modestly improve electrocardiographic detection of
LVH,22,23 and the product of Cornell
voltage and QRS duration (Cornell voltage-duration product)24,25—as
an approximation of the true area under the QRS complex26—further
enhances sensitivity of the ECG while maintaining high specificity, with a
sensitivity of 51% vs 31% for Sokolow-Lyon voltage when examined at a matched
specificity of 95%.24 As a consequence, Cornell
voltage-duration product criteria were used in combination with Sokolow-Lyon
voltage criteria21 to identify patients with
hypertension who are at increased risk of CV morbidity and mortality in the
Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study,
a prospective trial that demonstrated a greater reduction in CV events in
patients taking losartan than in those taking atenolol.28- 31

In the prespecified echocardiographic substudy of the LIFE study, the
presence of electrocardiographic LVH by Cornell product and/or Sokolow-Lyon
voltage criteria identified patients with hypertension having a greater than
70% likelihood of having echocardiographic LVH as well as those not fulfilling
the strict cutoff criteria for echocardiographic LVH but with high-normal
values of indexed left ventricular mass.32 Moreover,
regression of electrocardiographic LVH by Cornell product criteria was associated
with greater 1-year reductions in left ventricular mass and a higher likelihood
of regression of echocardiographic LVH in the LIFE study,15 suggesting
that lower values of electrocardiographic LVH criteria during serial evaluation
over time may predict improved outcome during antihypertensive therapy. Accordingly,
the present study examined whether lower in-treatment values of electrocardiographic
LVH as measured by Cornell product and Sokolow-Lyon voltage criteria are associated
with a reduced rate of major CV events in the LIFE study, independent of the
effects of BP change, treatment type, and severity of baseline electrocardiographic
LVH.28- 31

METHODS

Participants

The LIFE study28- 31 enrolled
patients with hypertension having electrocardiographic LVH by Cornell voltage-duration
product24,25 and/or Sokolow-Lyon
voltage criteria21 on a screening ECG in a
prospective, double-blind, randomized study large enough (n = 9193)
to have sufficient power (80%) to detect a difference of at least 15% in the
incidence of combined CV morbidity and mortality with use of losartan as opposed
to atenolol.28 As described in detail elsewhere,28- 31 patients
eligible for the LIFE study were men and women aged 55 to 80 years with previously
untreated or treated essential hypertension with mean seated BP in the range
of 160 to 200 mm Hg systolic, 95 to 115 mm Hg diastolic, or both, after 1
and 2 weeks of receiving placebo who had not experienced a myocardial infarction
(MI) or stroke within 6 months and did not require treatment with a β-blocker,
angiotensin-converting enzyme inhibitor, or AT1-receptor antagonist.
The study was approved by all ethics committees concerned. All participants
gave written informed consent.

Treatment Regimens

Blinded treatment was begun with losartan, 50 mg, or atenolol, 50 mg,
daily and matching placebo of the other agent, with a target BP of 140/90
mm Hg or lower. During clinic visits at frequent intervals for the first 6
months and at 6-month intervals thereafter, study therapy could be up-titrated
by addition of hydrochlorothiazide, 12.5 mg, followed by increase in blinded
losartan or atenolol to 100 mg/d. In patients whose BP was still not controlled,
additional open-label upward titration of hydrochlorothiazide and, if necessary,
institution of therapy with a calcium channel blocker or additional other
medications (excluding β-blockers, angiotensin-converting enzyme inhibitors,
or AT1-receptor antagonists) was added to the double-blind treatment
regimen.28

Electrocardiography

Electrocardiograms were obtained at study baseline, at 6 months, and
at yearly follow-up intervals until study termination or patient death. Electrocardiograms
were interpreted at the core laboratory at Sahlgrenska University Hospital/Östra,
Göteborg, Sweden, by experienced readers blinded to clinical information.
QRS duration was measured to the nearest 4 ms and the QRS amplitudes to the
nearest 0.5 mm (0.05 mV). The product of QRS duration × the
Cornell voltage combination (RaVL + SV3, with
8 mm added in women24,25) was
used with a threshold value of 2440 mm × ms to identify LVH.
After the LIFE trial was designed, studies were published suggesting a smaller
sex adjustment,33,34 and feedback
from LIFE investigators showed that otherwise-eligible patients had electrocardiographic
LVH by highly specific but insensitive Sokolow-Lyon voltage21 but
not by Cornell product criteria. Accordingly, changes were made in electrocardiographic
entry criteria for patients recruited after April 30, 1996 (n = 7708):
the sex adjustment of Cornell voltage was reduced from 8 to 6 mm and Sokolow-Lyon
voltage (SV1 + RV5/6) greater than 38 mm was
accepted for electrocardiographic eligibility.29

End Point Determination

The LIFE trial used a composite end point of CV death, nonfatal MI,
or nonfatal stroke, according to previously defined criteria.28 Potential
end points were ascertained and then verified by an expert end point committee
who were blinded to ECG results when classifying possible morbid events, as
previously described.28,31

Statistical Analyses

Data are presented as mean (SD) for continuous variables and as proportions
for categorical variables. Analyses of changes in mean values over time were
performed using repeated-measures analysis of variance. To test the hypothesis
that lower values of Cornell product and Sokolow-Lyon voltage during antihypertensive
therapy are associated with a reduction of clinical events, independent of
treatment type and magnitude of BP lowering, the relations of electrocardiographic
LVH criteria to the risk of developing the LIFE composite clinical end point
and its individual components were analyzed based on the intention-to-treat
principle; ie, all randomized patients were assessed for end points for the
duration of the study, regardless of protocol violations or adherence to study
medication.31 All patients enrolled in the
LIFE trial with a valid baseline ECG were included in the statistical analyses.
According to a prespecified statistical analysis plan, the relations of changing
levels of Cornell product and Sokolow-Lyon voltage to the risk of clinical
end points were assessed using Cox proportional hazards models,35 with
baseline and subsequent determinations of Cornell product and Sokolow-Lyon
voltage entered as time-varying covariates. Baseline Framingham risk score36 and a treatment group indicator were included as
standard covariates, and baseline and subsequent systolic and diastolic BP
measurements were entered as time-varying covariates. The adjusted hazard
ratios (HRs) for the incidence of the composite end point for Cornell product
and Sokolow-Lyon voltage treated as continuous variables were computed per
1-SD-of-the-mean lower values of the electrocardiographic criteria as the
antilogarithm of the estimated coefficient multiplied by the SD.37 The
95% confidence interval (CI) of each relative risk was calculated from the
estimated coefficients and their standard errors,38 and
Wald χ2 statistics and probability values were calculated.

The relationship of event rates over time to changing values of each
LVH criterion was illustrated by plotting event rates as functions of grouped
ranges of Cornell product and Sokolow-Lyon voltage using a modified Kaplan-Meier
method,39 with assignment to groups adjusted
at the time of each ECG performed based on the measurement of Cornell product
and Sokolow-Lyon voltage at those times. These modified Kaplan-Meier curves
are intended to illustrate the results of the time-varying covariate analyses.

For all tests, a 2-tailed P<.05 was required
for statistical significance. Data management and analyses were primarily
performed by the Clinical Biostatistics Department of Merck Research Laboratories
using SAS version 8 (SAS Institute Inc, Cary, NC), with independent validation
performed by 1 of the investigators (P.M.O.). All study data currently reside
in the Merck & Co Inc database.

RESULTS

After mean follow-up of 4.8 (SD, 0.9) years, 1096 of the 9193 patients
(11.9%) had documented LIFE primary end points of cardiovascular death, nonfatal
MI, or stroke. As previously reported,31 LIFE
patients were a mean age of 67 years, and 54% were women; 72% were previously
treated for hypertension and previous coronary, cerebral, or peripheral vascular
disease, and diabetes occurred in 16%, 8%, 6%, and 13% of these patients,
respectively, without difference between treatments.

Serial Assessment of BP and Electrocardiographic LVH

Baseline and serial assessments of mean systolic and diastolic BP, Cornell
product, and Sokolow-Lyon voltage are shown in Table 1. As expected based on the entry criteria for the LIFE study,
the mean systolic and diastolic BP, Cornell voltage-duration product, and
Sokolow-Lyon voltage were elevated at baseline and decreased substantially
during the first year in the LIFE study, concomitant with the institution
of protocol-based antihypertensive therapy. In subsequent years, BP continued
to decrease only slightly, whereas there were continued significant further
decreases in Cornell product and Sokolow-Lyon voltage between 12- and 24-month
ECGs, with small further decreases through the 60-month ECGs.

Table Graphic Jump LocationTable 1. Baseline and Follow-up Blood Pressure
and Electrocardiographic Left Ventricular Hypertrophy, by Cornell Voltage-Duration
Product and Sokolow-Lyon Voltage During Treatment in the LIFE Study*

Regression of Electrocardiographic LVH and CV Events

Lower in-treatment values of both Cornell voltage-duration product and
Sokolow-Lyon voltage during antihypertensive therapy were strongly associated
with decreased risk of CV morbidity and mortality (Table 2, Figure 1, and Figure 2). In Cox analyses adjusting only for
possible treatment effect (Table 2),
a 1050-mm × ms (1 SD of the baseline mean) lower Cornell product
was associated with a 15.4% lower risk of the composite CV end point, and
was a significant predictor of reduced risk of CV mortality, MI, and stroke.
In similar fashion, a 10.5-mm (1 SD of the baseline mean) lower Sokolow-Lyon
voltage during treatment was associated with a 20.4% lower risk of the composite
end point and was a significant predictor of decreased CV mortality, MI, and
stroke. Survival curves for Cornell product (Figure 1) and Sokolow-Lyon voltage criteria (Figure 2) depicting outcomes in varying quartiles of these measures
over the time-course of the study illustrate that higher in-treatment levels
of electrocardiographic LVH were associated with greater risks of CV morbidity
and mortality, whereas lower in-treatment levels of electrocardiographic LVH
were associated with lower rates of the composite end point, CV mortality,
MI, and stroke. After controlling for treatment with losartan or atenolol,
for baseline Framingham risk score, Cornell product, and Sokolow-Lyon voltage,
and for baseline and in-treatment systolic and diastolic BP, both lower in-treatment
Cornell product and Sokolow-Lyon voltage remained in the Cox analyses as significant
predictors of CV morbidity and mortality (Table
2). In these Cox models, a 1050-mm × ms lower Cornell
product was associated with a 14.5% decrease in the composite end point, a
22.0% lower risk of CV death, and 10% decreases in the rates of MI and stroke.
A 10.5-mm lower Sokolow-Lyon voltage was associated with a 16.6% decrease
in the composite end point, a 20.4% lower risk of CV mortality, a 10% decrease
in MI, and an 18.8% lower rate of stroke over the period of the study. Of
note, the predictive values of changing levels of both Cornell product and
Sokolow-Lyon voltage remained significant when examined separately in each
treatment group. Moreover, inclusion in the multivariate Cox models of baseline
QRS and QT interval duration and changing levels of uric acid as a time-varying
covariate—variables previously demonstrated to stratify risk in the
LIFE study40,41—did not
impact the relation of changing levels of Cornell product or Sokolow-Lyon
voltage to CV morbidity and mortality.

Figure 2. Rate of the Composite End Point,
Cardiovascular Mortality, Stroke, and Myocardial Infarction by Time-Varying
Categories of Sokolow-Lyon Voltage

Patient group assignment is adjusted at the time of each electrocardiogram,
based on the value of Cornell product at each time.

Because Cornell product and Sokolow-Lyon voltage each remained strongly
associated with lower risk of the composite end point and its individual components
(Table 2), the predictive value of lower
in-treatment values of both of these electrocardiographic criteria taken together
can be examined. After adjusting for treatment, Framingham risk score, and
BP determinations, a simultaneous 1-SD decrease in both Cornell product and
Sokolow-Lyon voltage was associated with a 29.1% decreased risk of the composite
end point (HR, 0.71; 95% CI, 0.64-0.80), a 38% decreased risk of CV mortality
(HR, 0.62; 95% CI, 0.53-0.72), an 18.9% lower rate of MI (HR, 0.81; 95% CI,
0.67-0.98), and a 26.8% decreased risk of stroke (HR, 0.73; 95% CI, 0.63-0.86).

COMMENT

This study demonstrates that lower values of electrocardiographic LVH
by Cornell product and/or Sokolow-Lyon voltage criteria during antihypertensive
therapy are associated with a lower likelihood of CV morbidity and mortality,
independent of treatment modality and of decreases in BP in a prospectively
studied population of patients with hypertension selected to be at increased
risk of CV events based on the presence of LVH on a screening ECG. In contrast,
persistence or development of high values of electrocardiographic LVH by these
criteria are associated with increased risk of CV morbidity and mortality.
These findings support the value of electrocardiographic LVH criteria for
assessing CV risk over time in patients with hypertension and suggest that
antihypertensive therapy targeted at regression or prevention of electrocardiographic
LVH by these criteria may improve prognosis.

Regression of Electrocardiographic LVH and Prognosis

A number of previous studies have demonstrated that regression of electrocardiographic
LVH and prevention of progression to LVH are associated with a reduced risk
of CV morbidity.2,3,12,13 An
observational study of 524 participants in the Framingham Heart Study with
electrocardiographic LVH by various criteria at a qualifying examination2 found that a significant decline in Cornell voltage
was associated with lower risk of CV disease, whereas a significant increase
in Cornell voltage identified individuals at increased risk of CV disease.
Prineas et al13 demonstrated that increases
in electrocardiographic LVH by Cornell product and Novacode criteria and incident
electrocardiographic LVH by these criteria were associated with increased
risk of mortality in men in the usual-care arm of the Multiple Risk Factor
Intervention Trial (MRFIT). In contrast, increases in Sokolow-Lyon voltage
were associated with decreased risk in this study.13 However,
these investigators averaged changes in electrocardiographic LVH criteria
over 6 years of follow-up, which could underestimate the predictive value
of serial increases or decreases in electrocardiographic measures over this
time period, and their findings were limited to men. In contrast, recent data
from the Heart Outcomes Prevention Evaluation (HOPE) trial3 provided
perhaps the strongest previous evidence supporting the hypothesis that regression
of electrocardiographic LVH improves prognosis, demonstrating that the combined
end point of either regression of electrocardiographic LVH or prevention of
progression to electrocardiographic LVH in response to ramipril-based therapy
was associated with reduced risk of death, MI, stroke, and congestive heart
failure. However, the usefulness of these findings is limited by the low prevalence
of electrocardiographic LVH in the HOPE trial,3 the
absence of adjustment for other clinical variables in outcome analyses, and
by the absence of specific data addressing the value of changes in Sokolow-Lyon
voltage for predicting outcome.

The present study supports the importance of serial measurement of electrocardiographic
LVH during antihypertensive treatment for risk stratification. We found that
significantly lower values of both Cornell product and Sokolow-Lyon voltage
were associated with 14.5% to 16.6% reductions in the incidence of major CV
morbidity and mortality over 4.8 years of follow-up, independent of primary
study assignment to losartan or atenolol, baseline Framingham risk score,
and of baseline and in-treatment levels of BP. Intriguingly, serial measures
of both Cornell product and Sokolow-Lyon voltage remained in the adjusted
Cox models for all end points, such that the combination of lower in-treatment
values of both electrocardiographic LVH criteria was associated with a greater
than 29% reduction in the composite end point of CV morbidity and mortality.

The strong, independent relation between lower values of electrocardiographic
LVH and reduced rates of CV events in the current study are paralleled by
findings from the echocardiographic substudy of LIFE, which provide evidence
of a similarly powerful association of changing left ventricular mass with
CV morbidity and mortality.42 As reported by
Devereux and colleagues42 in this issue of JAMA, 1-SD (25.3) lower values of indexed left ventricular
mass were associated with a 22% lower rate of the LIFE composite end point,
a 38% reduction in CV mortality, a 24% reduction in stroke, and a 15% lower
rate of MI. Taken together, these electrocardiographic and echocardiographic
findings demonstrate that the strong association between serial assessments
of LVH and CV outcomes is independent of the method used to serially assess
the degree of hypertrophy.

Methodological Issues

Several limitations of the present study warrant review. Use of Cornell
product and Sokolow-Lyon voltage criteria to select patients for the LIFE
study increased the baseline risk of the study population and, as a consequence,
the present findings may not be representative of those for hypertensive populations
with less-severe disease. In this context, it is important to note that the
prevalence of electrocardiographic LVH in 1746 ambulatory patients with hypertension
was 9.8% in men and 5.7% in women for Sokolow-Lyon voltage and 14.9% and 18.8%,
respectively, by Cornell product criteria.43 In
addition, the statistical phenomenon of regression to the mean44 may
impact the current findings, particularly in light of the use of values of
Cornell product and Sokolow-Lyon voltage above threshold levels to select
patients for the LIFE study, despite our attempt to minimize this problem
by using separate screening and baseline ECGs.28,29 As
a consequence of this selection process and the intrinsic variability of electrocardiographic
measurements,44- 47 it
is likely that both the degree of ECG LVH at baseline and the subsequent decrease
in electrocardiographic LVH during therapy were overestimated in some patients.
However, improved outcome was associated with regression of electrocardiographic
LVH despite these limitations, which would actually bias against our findings,
because these overestimations due to statistical fluctuations would lead to
a more conservative estimate of the impact of electrocardiographic LVH on
outcome. Moreover, assessment of risk based on electrocardiographic LVH criteria
considered as time-dependent covariates adjusts for both baseline and subsequent
levels of these variables, mitigating the impact of any overestimations.

Implications

These findings have important implications for the management of patients
with hypertension, beyond the demonstrated beneficial effect of losartan on
outcomes in the LIFE study.31 These data support
the use of Cornell product and Sokolow-Lyon voltage criteria to identify patients
with hypertension who are most likely to benefit from aggressive antihypertensive
therapy and suggest that serial evaluation of these criteria during treatment
can be used to monitor risk. These observations further suggest that antihypertensive
therapy targeted at regression or prevention of electrocardiographic LVH may
become an additional goal of therapy beyond that of lowering BP, in order
to further decrease the risk of CV morbidity and mortality.

Financial Disclosures: Drs Okin, Devereux,
and Nieminen have received grant support, honoraria for lectures about the
LIFE study, and funding for consulting and lecturing from Merck, respectively;
Dr Snapinn was a Merck employee.

Author Contributions: Dr Okin had full access
to all of the data in this study and takes responsibility for the integrity
of the data and the accuracy of the data analyses.

Funding/Support: The LIFE study was supported
in part by grant COZ-368 from Merck & Co Inc.

Role of the Sponsor: All study data reside
in the Merck & Co Inc database. Merck provided the study authors with
free access to all of the data; the authors were free to interpret data and
write the paper and the outcome was independently validated by the steering
committee statistician. The sponsor agreed to support the performance of the
study, at which time it was also agreed that the findings would be published
by the investigators regardless of the results. The decision to publish the
paper, the choice of analyses to include, and the drafting of the manuscript
were wholly controlled by Dr Okin and coauthor members of the LIFE Electrocardiographic
Working Group.

Figure 2. Rate of the Composite End Point,
Cardiovascular Mortality, Stroke, and Myocardial Infarction by Time-Varying
Categories of Sokolow-Lyon Voltage

Patient group assignment is adjusted at the time of each electrocardiogram,
based on the value of Cornell product at each time.

Tables

Table Graphic Jump LocationTable 1. Baseline and Follow-up Blood Pressure
and Electrocardiographic Left Ventricular Hypertrophy, by Cornell Voltage-Duration
Product and Sokolow-Lyon Voltage During Treatment in the LIFE Study*

Letters

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